1. INTRODUCTION:

In the last decade, significant advancements have transformed the therapeutic landscape for patients with various cardiovascular and thromboembolic disorders.¹Despite these developments, antithrombotic therapy remains a cornerstone in the prevention and management of arterial and venous thrombotic diseases. These agents, comprising anticoagulants and antiplatelets, are widely prescribed in both acute and chronic settings to reduce the risk of clot formation and associated complications.² More than one billion people worldwide have an indication for antithrombotic therapy.³ According to a report by the IQVIA Institute, antithrombotic agents consistently rank among the top ten therapeutic classes globally in terms of both spending and volume.⁴ In the United Arab Emirates (UAE), a recent study of atrial fibrillation (AF) patients (FLOW-AF Registry) found that 100% of 198 newly diagnosed nonvalvular AF patients received an antithrombotic, with a total of 260 treatments recorded: 73.2% received non-vitamin K antagonist oral anticoagulants, 42.4% received antiplatelet agents, and only 8.6% were prescribed vitamin K antagonists.⁵ Additionally, a separate Dubai-based analysis reported that antiplatelet drugs and other anticoagulants were among the three most frequently used medications in stable outpatient care, with 38.5% of patients receiving other anticoagulants and 38.0% receiving antiplatelet drugs.⁶ However, their widespread use is often accompanied by significant concerns related to adverse drug reactions (ADRs), drug-drug interactions (DDIs), and variable dosing patterns that may adversely impact clinical outcomes.

Complications associated with antithrombotic therapy, particularly anticoagulants, account for a significant proportion of emergency department visits, hospital admissions, and preventable harm.^7-11 In the United States (US), the estimated cost of hospital admissions related to these complications exceeds $2.5 billion.^10-11 Both randomized controlled trials and real-world studies consistently show that all antithrombotic therapies carry a risk of bleeding complications, which can vary in severity and affect different anatomical sites, ranging from mild bruising to severe, life-threatening hemorrhages.^12-13In addition to bleeding complications, antithrombotic agents are associated with other ADRs, such as thrombocytopenia and hypersensitivity reactions. Prolonged anticoagulant use has also been linked to decreased bone mineral density, particularly among patients with cancer or underlying cardiovascular disease.¹⁴ Furthermore, these agents are associated with gastrointestinal disturbances, including nausea, dyspepsia, and gastric ulcer formation, especially with long-term use.¹⁵ These medications are also susceptible to significant DDIs, which can exacerbate bleeding risk or reduce therapeutic efficacy, complicating treatment management. Data on ADRs and DDIs in the Middle East show prevalence patterns and severity similar to global trends.^16-17 For example, a study conducted in the UAE reported that 15% of ADR-related hospitalizations were attributed to antithrombotic agents, with anticoagulants responsible for 9% and antiplatelets for 6%.¹⁶

Another critical issue in the use of antithrombotic agents is ensuring appropriate dosing. A meta-analysis on the real-world prevalence of direct oral anticoagulant (DOAC) off-label dosing in patients with AF reported that 14-32% of patients received off-label doses across various regions, including Asia, North America, and Europe.¹⁷ The SAGE-AF study, a real-world multicenter study involving AF patients prescribed DOACs (apixaban, rivaroxaban, dabigatran), also reported inappropriate dosing among 23% of participants, with 78% of these cases being underdosed and 22% overdosed.¹⁸ Both underdosing and overdosing are associated with significant clinical risks, leading to increased morbidity and mortality. A systematic review found that overdosing with DOACs was linked to all-cause mortality and an elevated risk of bleeding, while underdosing was associated with increased cardiovascular hospitalizations.¹⁹Factors such as renal function, age, body weight, polypharmacy (particularly the use of multiple antithrombotic agents), DDIs, and adherence to clinical guidelines play a crucial role in determining appropriate dosing and optimizing clinical outcomes.²⁰

Comparing the Prescribed Daily Dose (PDD) to the Defined Daily Dose (DDD) is particularly essential in the evaluation of antithrombotic drug use, as these medications typically have narrow therapeutic ranges and variable dosing requirements depending on the indication and individual patient factors. The DDD is a fixed unit of measurement independent of price and dosage form, which enables the assessment of trends in drug consumption and facilitates comparisons between population groups.The PDD is defined as the average daily amount of a drug that is actually prescribed,²¹ and comparing the PDD with the DDD can help identify deviations from expected patterns and evaluate the appropriateness of prescribing.²² Several studies have reported discrepancies between PDD and DDD. For instance, a study from Malaysia reported complete alignment between antithrombotic prescribed doses and WHO-defined DDDs.²³ In contrast, a study from India highlighted that anticoagulants were often prescribed at doses that did not match World Health Organization (WHO)-defined DDDs,²⁴ reflecting real-world variations in clinical practice. Furthermore, a 16-year longitudinal study from Denmark showed that the antithrombotic drug use increased from 64 to 96 DDDs per 1,000 inhabitants per day.²⁵

Close monitoring of antithrombotic agents is crucial for maintaining anticoagulation within the desired therapeutic range, thereby minimizing the risk of thromboembolic complications.²⁶ Traditional drugs like warfarin and heparin have narrow therapeutic windows, necessitating precise laboratory-based monitoring with prothrombin time (PT), international normalized ratio (INR), and activated partial thromboplastin time (aPTT). In contrast, many newer anticoagulants (e.g., DOACs) exert their antithrombotic effects through specific inhibition of clotting factors and interactions with vascular endothelium and proteins and do not significantly affect conventional coagulation test results, necessitating the use of more sophisticated monitoring methods.²⁷ Moreover, studies have shown that proper monitoring of warfarin therapy not only reduces the incidence of ADRs but also enhances patient adherence to treatment.²⁶

While the benefits and challenges of antithrombotic therapy are well recognized globally, notable gaps remain in the literature regarding their real-world use in the Middle East, including the UAE. Specifically, limited published evidence exists on the appropriateness of dosing, the types and frequency of ADRs and DDIs in routine care, and the correlation between coagulation parameters and clinical outcomes. Most available data are derived from studies in North America, Europe, or East Asia,^23,28-31 which may not be directly applicable to the UAE due to differences in patient demographics, prescribing practices, and healthcare infrastructure. This represents a critical knowledge gap that underscores the need to evaluate the safety and efficacy of antithrombotic therapy in the UAE. Accordingly, the present study was designed to (1) calculate the PDD and compare it with the DDD according to WHO guidelines, (2) assess ADRs and DDIs, and (3) analyze clinical outcomes associated with antithrombotic use. By addressing these objectives, the study aims to generate evidence to inform safer and more effective therapy in clinical settings.

2. MATERIALS AND METHODS:

2.1 Study setting and period:

The study was carried out at a private academic hospital in Ajman, UAE, over a seven-month period from January to July 2023. Data were gathered across various medical specialties, including cardiology, general medicine, nephrology, surgery, neurology, orthopedics, pulmonology, and the Intensive Care Unit (ICU).

2.2 Study design and population:

A prospective observational study was conducted to evaluate the utilization patterns, safety, and clinical outcomes associated with antithrombotic therapy. The study included adult patients aged 18 years and older, of any gender, who were admitted to the specified medical disciplines with various underlying conditions and received at least one antithrombotic agent for either treatment or prophylaxis during their hospital stay. Exclusion criteria comprised outpatients, individuals with end-stage renal disease undergoing dialysis while on antithrombotic therapy, pregnant or lactating women, and pediatric or adolescent patients below 18 years of age.

2.3 Sample size calculation and sampling method:

The sample size was determined using Raosoft software, which estimated a required sample of 125 participants, ensuring a 95% confidence interval, a 5% margin of error, and a 15% contingency. A convenience sampling approach was utilized to recruit participants based on their availability throughout the study duration.

2.4 Study instrument:

Data collection was carried out using a structured form designed after an extensive review of literature on antithrombotic utilization. This form documented comprehensive details, including patient demographics, clinical and surgical characteristics, laboratory and radiological findings, and medication-related information such as drug names, indications, dosages, dosage forms, and routes of administration. Additionally, clinical outcomes, reported ADRs, and potential DDIs associated with antithrombotic therapy were systematically compiled.

2.5 Data collection procedure:

Patient enrollment numbers were retrieved from prescription records, and relevant clinical, laboratory, and treatment-related data were collected from multiple sources, including case notes, treatment charts, laboratory reports, and medical and prescription records. Patients were closely monitored from the day of admission until discharge, with daily reviews of their records to ensure comprehensive documentation of all relevant information, including any adjustments made to their treatment during hospitalization.

Sociodemographic information, such as gender, age, ethnicity, department of admission, and health insurance status, was extracted from the hospital’s electronic medical records. Clinical data encompassed body mass index (BMI), past medical history, reasons for hospitalization, current diagnosis, Charlson Comorbidity Index (CCI) scores, duration of hospital stay, and diagnostic parameters associated with antithrombotic therapy, including PT, aPTT, INR, D-dimer levels, and markers of renal and hepatic function. Additionally, medication-related details, including generic names, therapeutic indications, prescribed dosages, pharmaceutical formulations, frequency of administration, route of administration, duration of therapy, and justification for use, were systematically recorded.

Drug utilization patterns were analyzed using the WHO Anatomical Therapeutic Chemical/Defined Daily Dose (ATC-DDD) methodology. The PDD was determined by dividing the total administered dose by the duration of therapy and was subsequently expressed as the PDD:DDD ratio to facilitate comparisons with the WHO-defined DDD for each antithrombotic agent. The DDD values used for this study were based on the recalculated DDDs provided by WHO. A PDD:DDD ratio of 1 indicates that the prescribed dose aligns with the WHO-defined standard. Ratios exceeding 1 suggest the administration of higher-than-standard doses, which may be influenced by patient-specific factors, loading doses, clinical guidelines, or institutional protocols for specific conditions. Conversely, ratios below 1 may indicate under-dosing, potentially due to conservative prescribing practices or patient-specific adjustments.

Throughout the study, patients’ medication regimens were continuously assessed using UpToDate to identify potential DDI involving antithrombotics, as well as to document any reported ADRs. Clinical outcomes were thoroughly evaluated, determining whether patients met the intended therapeutic goals and were discharged in accordance with the directives of the physician.

2.6 Ethical considerations

The study protocol received ethical approval from the Institutional Review Board of Gulf Medical University (Reference No: IRB/COP/STD/30/OCT-2022), ensuring adherence to data protection policies, patient safety measures, and established ethical guidelines. As a non-interventional study, no alterations or interventions were made to patients’ treatment as part of the research protocol. To uphold confidentiality and privacy, all patient identifiers, including names and personal identification numbers, were safeguarded and not disclosed to any third parties, in strict compliance with ethical regulations.

2.7 Statistical analysis:

The data were exported from Microsoft Excel to SPSS version 29.0 (IBM Corp, Armonk, NY, USA) for statistical analysis. Continuous variables were summarized using descriptive statistics such as mean, standard deviation, median, and interquartile range (IQR). Meanwhile, categorical variables were analyzed and reported as frequencies and percentages. Simple t-test was employed to compare the PDD with the DDD for each antithrombotic agent and a p-value of less than 0.05 was considered statistically significant.

3. RESULTS:

Figure 1 illustrates the process of patient selection and follow-up during the study. Of the 130 patients admitted during the study period and prescribed antithrombotic therapy, 100 met the study criteria and were included in the study. These patients were followed up during their hospitalization, and a comprehensive review of their medical records was conducted to collect relevant data.

Figure 1. CONSORT diagram: Patient selection and follow up process

3.1. General sociodemographic and clinical characteristics of the study population:

The sociodemographic characteristics of the study population are summarized in Table 1. Most patients receiving antithrombotic treatment were male (82%) and aged 41-50 years (34%), with a mean age of 52.39 years. Patients were treated across various medical specialties, with the Cardiology department managing the highest proportion (59%). Overweight and obese categories were equally prevalent, each representing 40% of the cohort. A significant proportion of patients (88%) had pre-existing medical conditions, with 53% having 4-6 comorbidities. The most common current active diagnoses were circulatory system diseases (38%), with 50% demonstrating a mild disease burden based on the CCI. The majority (60%) had a short stay of three days or less, while the mean hospital stay was 3.6 days. Half of the patients were prescribed between 5 and 9 medications, while 42% received 10 or more, with a mean of 9.11 medications.

Table 1. Sociodemographic and clinical characteristics of patients receiving antithrombotic therapy

Variables	Categories	Number of patients (%)
Gender	Male	82 (82.00)
Gender	Female	18 (18.00)
Age group (in years)	≤30	3 (3.00)
	31-40	11 (11.00)
	41-50	34 (34.00)
	51-60	30 (30.00)
	61-70	13 (13.00)
	>70	9 (9.00)
	Mean±SD	52.39±11.9137
	Median (IQR)	51 (14)
	Range	28-86
Department	Cardiology	59 (59.00)
	General medicine	17 (17.00)
	General surgery	1 (1.00)
	Nephrology	1 (1.00)
	Neurology	9 (9.00)
	Orthopaedic	4 (4.00)
	Pulmonology	6 (6.00)
	ICU	3 (3.00)
Health insurance coverage	Yes	82 (82.00)
Health insurance coverage	No	18 (18.00)
BMI (in kg/m²)	<18.5	0 (0.00)
	18.5-24.9	20 (20.00)
	25-29.9	40 (40.00)
	30-39.9	35 (35.00)
	≥40	5 (5.00)
	Mean±SD	29.16±6.0204
	Median (IQR)	27.68 (6.0940)
	Range	20.8-67.2
Past medical history	Yes	88 (88.00)
Past medical history	No	12 (12.00)
Number of current active diagnoses	≤3	35 (35.00)
	4-6	53 (53.00)
	≥7	12 (12.00)
	Mean±SD	4.24±1.7298
	Median (IQR)	4 (2)
	Range	1-9
Current active diagnoses*	Circulatory system diseases	160 (38.09)
	Endocrine, nutritional, metabolic diseases	95 (22.61)
	Respiratory system diseases	38 (9.04)
	Neuropsychiatric disorders	12 (2.86)
	Skin and musculoskeletal diseases	12 (2.85)
	Genitourinary system diseases	12 (2.85)
	Digestive system diseases	11 (2.61)
	Others	80 (19.05)
CCI score	0 (No comorbidities)	3 (3.00)
	Mild (1-2)	50 (50.00)
	Moderate (3-4)	35 (35.00)
	Severe (≥5)	12 (12.00)
	Mean±SD	2.72±1.6148
	Median (IQR)	2 (2)
	Range	0-9
Duration of hospital stay (in days)	≤3	60 (60.00)
	4-6	31 (31.00)
	7-9	8 (8.00)
	≥10	1 (1.00)
	Mean±SD	3.6±1.8202
	Median (IQR)	3 (2)
	Range	1-10
Total number of medications prescribed per patient	<5	8 (8.00)
	5-9	50 (50.00)
	≥10	42 (42.00)
	Mean±SD	9.11±3.6011
	Median (IQR)	9 (5)
	Range	3-19

Abbreviations: BMI: Body Mass Index, CCI: Charlson Comorbidity Index, SD: Standard Deviation, ICU: Intensive Care Unit, IQR: Interquartile Range

* With regard to the diagnoses, some patients had presented with multiple conditions

3.2 Pattern of antithrombotic utilization:

Table 2 presents the utilization pattern of antithrombotic therapy among the study population. Anticoagulant therapy was administered to 33% of patients, with enoxaparin (72%) being the most commonly prescribed anticoagulant, followed by unfractionated heparin (UFH) (13%), and rivaroxaban (9%). A total of 67% of patients received antiplatelet therapy, with aspirin being the most frequently prescribed agent (51%), followed by ticagrelor (23%), and clopidogrel (21%).

Table 2. Utilization pattern of antithrombotic therapy among patients

Prescribed antithrombotic		Number of patients (%)	Total (%)
Anticoagulant therapy	Apixaban	2 (2.90)	69 (32.86)
	Rivaroxaban	6 (8.70)
	Warfarin	2 (2.90)
	Enoxaparin	50 (72.46)
	UFH	9 (13.04)
Antiplatelet therapy	Aspirin	72 (51.06)	141 (67.14)
	Clopidogrel	30 (21.28)
	Ticagrelor	32 (22.70)
	Tirofiban	7 (4.96)

Abbreviations: UFH: Unfractionated Heparin

*Total percentage exceeds 100% because some patients received multiple antithrombotics during their treatment

3.3. Calculation of PDD and comparison with DDD:

Table 3 presents a comparative analysis of the PDD and DDD for various antithrombotic medications across different medical indications, along with the calculated PDD:DDD ratios. Among vitamin K antagonists, warfarin was prescribed for arrhythmia at a PDD of 4.5 mg (PDD:DDD ratio 0.6), indicating a lower than standard dose, and for heart valve disease at 8 mg (ratio 1.0667), reflecting closer alignment with standard dosing recommendations. For heparin-based anticoagulants, UFH was used for ischemic heart disease (IHD) with a PDD of 11,395.56 IU, corresponding to a PDD:DDD ratio of 1.1396, indicating a slightly higher dose than the WHO-defined standard. Enoxaparin was extensively used across multiple conditions, with the highest doses observed in pulmonary embolism (PE) at 12,666.67 IU, IHD at 11,727.27 IU, and arrhythmia at 11,000 IU. These corresponded to high PDD:DDD ratios of 6.3333 for PE, 5.8636 for IHD, and 5.5 for arrhythmia. Lower doses of 4,000 IU were noted in conditions such as heart valve disease, pneumonia, pulmonary fibrosis, bone fractures, and severe sepsis. The p-value for enoxaparin use (<0.0001) indicated a statistically significant difference between the PDD and the WHO-defined DDD, highlighting the need for closer monitoring. Among direct factor Xa inhibitors, rivaroxaban was prescribed at higher doses for PE (30 mg, PDD:DDD ratio 1.5), standard doses for IHD and arrhythmia (20 mg, ratio 1), and lower doses for cerebral infarction (10 mg, ratio 0.5), indicating condition-specific dosing with adherence to standard recommendations in IHD and arrhythmia but deviations in PE and cerebral infarction. Similarly, apixaban was prescribed at 5 mg for IHD and 2.5 mg for heart failure (HF), corresponding to lower PDD:DDD ratios of 0.5 and 0.25, respectively, with a statistically significant p-value (0.0377), indicating a conservative dosing strategy for these conditions. For platelet aggregation inhibitors, clopidogrel was prescribed for multiple indications, with the highest dose for cerebral infarction (150 mg) and the lowest for HF (75 mg). It showed a PDD:DDD ratio exceeding 1 across nearly all conditions except HF, with the highest ratios in IHD (1.5715) and cerebral infarction (2.0). The statistically significant p-value (0.0046) indicates that higher-than-standard doses were frequently prescribed. Aspirin was widely prescribed, with PDDs ranging from 91.67 mg for HF to 166.67 mg for cerebral infarction, and showed PDD:DDD ratios exceeding 1 across all conditions. The significant p-value (<0.0001) indicates a notable difference between PDD and DDD, suggesting potential overprescription that may require clinical attention. Among GP IIb/IIIa inhibitors, tirofiban was used at 41.35 mg for IHD, corresponding to a PDD:DDD ratio of 4.135, indicating substantially higher prescribed doses than the WHO-defined standard. In contrast, ticagrelor was prescribed at 174.38 mg for IHD, with a PDD:DDD ratio close to 1, indicating adherence to standard dosing guidelines.

Table 3. Comparison of estimated PDD and DDD for antithrombotic therapy across various indications

Major group of antithrombotic	Individual antithrombotic	ATC code	Indication	Mean PDD	DDD	PDD:DDD	P value
Vitamin K antagonists	Warfarin (mg)	B01AA03	Arrhythmia	4.5	7.5	0.6	0.5492
			Heart valve disease	8		1.0667
			Overall	6.25		0.8333
Heparin group	UFH (IU)	C05BA03	IHD	11395.56	10000	1.1396	0.4845
	UFH (IU)	C05BA03	Overall	11395.56	10000	1.1396	0.4845
	Enoxaparin (IU)	B01AB05	IHD	11727.27	2000	5.8636	<0.0001^*
			Arrhythmia	11000		5.5
			HF	5000		2.5
			Heart valve disease	4000		2
			PE	12666.67		6.3333
			Pneumonia	4000		2
			Pulmonary fibrosis	4000		2
			Kidney disease	6000		3
			Bone fracture	4000		2
			Severe sepsis	4000		2
			Overall	6639.39		3.3197
Direct factor Xa inhibitors	Rivaroxaban (mg)	B01AF01	IHD	20	20	1	0.3409
			Arrhythmia	20		1
			Cerebral infarction	10		0.5
			PE	30		1.5
			Overall	20		1
	Apixaban (mg)	B01AF02	IHD	5	10	0.5	0.0377^*
			HF	2.5		0.25
			Overall	3.75		0.375
Platelet aggregation inhibitors	Clopidogrel (mg)	B01AC04	IHD	117.86	75	1.5715	0.0046^*
			HF	75		1
			Cerebral infarction	150		2
			Overall	114.29		1.5239
	Aspirin (mg)	B01AC06	IHD	106.77	75	1.4236	<0.0001^*
			HF	91.67		1.2223
			Heart valve disease	100		1.3333
			Cerebral infarction	166.67		2.2223
			Pneumonia	100		1.3333
			Bone fracture	100		1.3333
			Overall	110.85		1.478
	Tirofiban (mg)	B01AC17	IHD	41.35	10	4.135	0.0538
	Tirofiban (mg)	B01AC17	Overall	41.35	10	4.135	0.0538
	Ticagrelor (mg)	B01AC24	IHD	174.38	180	0.9688	0.1556
	Ticagrelor (mg)	B01AC24	Overall	174.38	180	0.9688	0.1556

Abbreviations: ATC code: Anatomical Therapeutic Chemical code, CAD: Coronary Artery Disease, DDD: Defined Daily Dose, HF: Heart Failure, IHD: Ischemic Heart Disease, IU: International Units, MI: Myocardial Infarction, PDD: Prescribed Daily Dose, PE: Pulmonary Embolism, UFH: Unfractionated Heparin

* A p-value below 0.05 indicates statistical significance

Table 5. Profile analysis of ADRs reported with antithrombotic agents

Primary implicated drugs	Concomitant medications	ADRs	Type	Number of patients (%)	Dechallenge	Rechallenge
Anticoagulants
Warfarin		High INR	Type A	1 (4.76)	No	NA
Warfarin		Severe headache	Type A	1 (4.76)	No	NA
Enoxaparin		Hematuria	Type A	3 (14.29)	No (2) Yes (1)	NA (2) No (1)
		Bleeding at injection site	Type A	1 (4.76)	Yes	No
		Red colored skin lesion	Type A	1 (4.76)	No	NA
	Rivaroxaban	Thrombocytopenia	Type A	1 (4.76)	No	NA
Rivaroxaban	Enoxaparin	Hematuria	Type A	1 (4.76)	No	NA
Apixaban		Hematuria	Type A	1 (4.76)	No	NA
Apixaban		Thrombocytopenia	Type A	1 (4.76)	No	NA
Antiplatelets
Clopidogrel		Chest pain	Type A	1 (4.76)	No	NA
Clopidogrel	Aspirin	Thrombocytopenia	Type A	2 (9.52)	No	NA
Aspirin		Severe vertigo	Type A	1 (4.76)	Yes	Yes
		Dizziness	Type A	1 (4.76)	No	NA
		Vomiting	Type A	2 (9.52)	No (1) Yes (1)	NA (1) Yes (1)
Tirofiban	Ticagrelor	High aPTT level	Type A	1 (4.76)	No	NA
Tirofiban	Ticagrelor	Hematuria	Type A	1 (4.76)	Yes	No
Ticagrelor		Dyspnea	Type A	1 (4.76)	No	NA

Table 5 continue

Primary implicated drugs	Causality	Severity	Seriousness	Predictability	Preventability	Fate of primary implicated drug	Treatment given
Anticoagulants
Warfarin	Possible	Level 2	Non-serious	Predictable	Definitely preventable	Dose altered	No
Warfarin	Possible	Level 1	Non-serious	Predictable	Probably preventable	Dose altered	Yes
Enoxaparin	Possible (2) Probable (1)	Level 2 (2) Level 1 (1)	Non-serious	Predictable	Probably preventable	No change (2) Drug withdrawn (1)	No
	Probable	Level 2	Non-serious	Predictable	Probably preventable	Drug withdrawn	Yes
	Probable	Level 2	Non-serious	Predictable	Probably preventable	No change	Yes
	Possible	Level 1	Non-serious	Not predictable	Probably preventable	No change	No
Rivaroxaban	Possible	Level 1	Non-serious	Predictable	Probably preventable	No change	No
Apixaban	Possible	Level 2	Non-serious	Predictable	Probably preventable	No change	No
Apixaban	Possible	Level 2	Non-serious	Predictable	Probably preventable	No change	No
Antiplatelets
Clopidogrel	Possible	Level 1	Non-serious	Predictable	Probably preventable	No change	No
Clopidogrel	Possible	Level 2	Non-serious	Not predictable	Probably preventable	No change	No
Aspirin	Possible	Level 1	Non-serious	Predictable	Probably preventable	No change	Yes
	Possible	Level 1	Non-serious	Predictable	Probably preventable	No change	No
	Possible	Level 1	Non-serious	Predictable	Probably preventable	No change	No (1) Yes (1)
Tirofiban	Possible	Level 2	Non-serious	Not predictable	Probably preventable	No change	No
Tirofiban	Possible	Level 2	Non-serious	Predictable	Probably preventable	Drug withdrawn	No
Ticagrelor	Possible	Level 1	Non-serious	Predictable	Probably preventable	No change	No

Abbreviations: ADRs: Adverse Drug Reactions, aPTT: Activated Partial Thromboplastin Time, INR: International Normalized Ratio, NA: Not Applicable

4. DISCUSSION:

The findings from this prospective hospital-based study provide valuable real-world insights into the utilization patterns, safety, and clinical outcomes of antithrombotic agents in routine clinical practice. Our findings indicate that 67% of patients received antiplatelet therapy, reflecting the high prevalence of arterial thrombotic conditions, which are primarily managed with these agents. Aspirin was the most commonly prescribed antiplatelet, followed by ticagrelor, aligning with standard dual antiplatelet therapy regimens recommended for acute coronary syndrome (ACS) and post-percutaneous coronary intervention. The relatively low prescription rate of tirofiban (5%) suggests its use was restricted to high-risk cases.³² Overall, the prescribing patterns in our study are largely consistent with findings from previous research.^33-36 Anticoagulant-only therapy accounted for 33% of prescriptions, with enoxaparin (72%) being the most frequently used anticoagulant. This preference is likely due to its ease of administration and favorable pharmacokinetic properties. Rivaroxaban (9%) and apixaban (3%) were primarily used as alternatives to warfarin, owing to their predictable pharmacokinetics, fewer drug interactions, and lack of routine monitoring requirements. Similar utilization patterns have been reported in studies from Italy³³ and India,³⁴ reinforcing these prescribing trends.

Warfarin exhibited varying PDD:DDD ratios depending on the medical indication. For arrhythmia, the PDD of 4.5 mg was notably lower than the WHO-defined DDD of 7.5 mg, resulting in a PDD:DDD ratio of 0.6. This suggests a more conservative dosing strategy, likely influenced by concerns over bleeding risk or individualized INR targets. In contrast, for heart valve disease, warfarin was prescribed at a higher dose (8 mg), yielding a PDD:DDD ratio of 1.07. This aligns with the need for more intensive anticoagulation to prevent thrombotic complications in patients with prosthetic heart valves. A similar trend has been observed in other published data.^35,37-38 Overall, the average PDD:DDD ratio was 0.83, which is consistent with findings from a study conducted in Nepal.³⁵ This suggests that warfarin is typically prescribed at lower doses than the WHO-defined DDD, possibly due to concerns about bleeding risks, individualized INR targets, or regional clinical guidelines favoring conservative anticoagulation. Among the DOACs, apixaban has demonstrated a favorable safety and efficacy profile. In our study, apixaban had the lowest PDD:DDD ratio, well below 1, indicating it may be under-prescribed or used at lower-than-standard doses. This could be due to prescriber hesitancy, lack of awareness, or institutional preference for traditional agents. Additionally, apixaban has specific renal dosing requirements that are sometimes overlooked or inconsistently applied in clinical practice. Evidence from studies involving large, privately insured populations has shown that, despite a high risk of stroke, more than one-third of patients with AF and no apparent contraindications were not prescribed an oral anticoagulant. Furthermore, studies have indicated that low-dose apixaban is associated with an increased risk of all-cause mortality compared to warfarin.^39-40 The utilization of UFH and enoxaparin varied based on the underlying condition, reflecting differences in therapeutic goals and pharmacokinetic properties. In IHD, UFH had a PDD:DDD ratio of 1.14, which aligns with findings from the Nepal study,³⁵ indicating a tendency for slightly higher-than-standard doses in clinical practice. This minor deviation may result from patient-specific factors such as weight, renal function, or adherence to treatment protocols, particularly in ACS, where higher UFH doses are often required for rapid anticoagulation and procedural safety. Similarly, enoxaparin demonstrated significantly elevated overall PDD:DDD ratios (p < 0.0001), indicating that it was prescribed at much higher doses than the standard, possibly due to weight-based dosing, illness severity, or institutional treatment protocols. The PDD:DDD ratio was especially high for PE, IHD, and arrhythmia, suggesting substantially higher prescribed doses compared to the standard prophylactic DDD. In contrast, much lower doses were used for conditions such as heart valve disease, pneumonia, pulmonary fibrosis, bone fractures, and severe sepsis, with a PDD:DDD ratio of 2.0, reflecting a more cautious approach.^41-42

Aspirin, clopidogrel, and tirofiban also showed notable deviations from the standard DDD. Aspirin and clopidogrel exhibited PDD:DDD ratios that diverged from 1, likely reflecting variability in prophylactic versus therapeutic dosing. For example, aspirin is typically used in low doses (75-100 mg daily) for cardiovascular prevention, but higher doses are employed in acute settings, resulting in a wider PDD:DDD range.⁴² Tirofiban had the highest PDD:DDD ratio in our study, exceeding 4, indicating that it was prescribed at doses substantially higher than the WHO-defined standard. In the US, the standard dose involves a high bolus (25 µg/kg over 3 minutes) followed by a maintenance infusion of 0.15 µg/kg/min for up to 24 hours. In contrast, the European Union uses a slower infusion protocol (0.4 µg/kg/min for 30 minutes, then 0.1 µg/kg/min for up to 48 hours).⁴³Despite these differences, the doses used in our study were even higher than both standard approaches, which may be attributed to institutional preferences for more aggressive dosing, the need for faster and more potent platelet inhibition, or efforts to provide enhanced thrombotic protection in patients undergoing invasive procedures.

During the study, the incidence of ADRs was 17%, with an overall ADR burden of 21% when accounting for multiple occurrences per patient. The most affected organ systems were renal and urinary disorders (hematuria, 29%), blood and lymphatic system disorders (thrombocytopenia, 19%), and gastrointestinal disorders (vomiting, 10%). A similar pattern of ADRs has been reported across different studies.^7-11 While hematuria was the most frequently reported ADR in both our study and that of Kassere et al.,³⁶ the study from the United States¹⁰ primarily reported abnormal coagulation parameters, more generalized bleeding events, and thrombocytopenia. Anticoagulants were responsible for 52% of all ADRs, with enoxaparin being the most frequently implicated agent (accounting for 55% of anticoagulant-related ADRs). Antiplatelet agents contributed to 48% of ADRs, with aspirin being the most common offender (40% of antiplatelet-related ADRs). The majority of ADRs were assessed as mild and non-serious. Variations in the severity and type of anticoagulant-associated ADRs have been reported across different studies.^7-11 In both our study and that by Kassere et al.,³⁶ low molecular weight heparin (LMWH), particularly enoxaparin, was the predominant cause of ADRs, which were generally mild to moderate in nature. In contrast, a study conducted in the United States¹⁰ identified unfractionated heparin and warfarin as the most commonly implicated anticoagulants, with more severe ADRs that often necessitated blood transfusion. In a study conducted in India by Rayees et al. to estimate the incidence of ADRs reported in the general medicine department, the anticoagulant warfarin accounted for 1.8% of reactions.⁴⁴ These discrepancies may be attributed to differences in the types of anticoagulants used, patient populations, monitoring protocols, ADR reporting criteria, medication errors, and underlying genetic factors. All ADRs were Type A (augmented), with 76% deemed possible in causality assessments, and most being predictable (81%) and probably preventable (90%), indicating potential to enhance prescribing and monitoring practices. Management was conservative in 76% of cases, likely due to the need to maintain antithrombotic therapy and the mild nature of most reactions. Notably, 33% occurred without identifiable risk factors. Among recognized factors, intercurrent diseases and polypharmacy were most common (29% each), followed by advanced age (9%). Although findings align with pharmacovigilance principles, no studies specifically addressing ADR classification, causality, predictability, management, and risk factors for antithrombotic agents were identified, limiting corroboration.

The analysis of potential DDIs within our study cohort revealed a moderate interaction burden (1.5), with 15 DDIs identified among 10 patients, corresponding to a prevalence of 10%. This is significantly lower than the prevalence reported by Apsīte et al., where 49.7% of patients were at increased risk for potential DDIs.⁴⁵ However, our findings were consistent with the study by Jagadeesan et al., who reported anticoagulants as the fifth major contributor to DDIs, accounting for 9% of cases.⁴⁶ Similarly, in a prospective interventional study conducted in a tertiary care hospital in India, anticoagulants and antiplatelets accounted for 10.63% of interactions identified in ICU prescriptions.⁴⁷ In our study, enoxaparin and clopidogrel were the most frequently implicated agents, with enoxaparin alone accounting for 27% of all interactions. This contrasts slightly with findings from other studies, where warfarin is more commonly identified as the primary anticoagulant associated with DDIs.^45,48-49 A possible explanation for this discrepancy is the lower utilization of warfarin in our patient population. Nonetheless, the classes of medications associated with DDIs involving antithrombotic agents were largely consistent with those reported in the existing literature.^45,48-49 Additionally, we found that 60% of interactions required therapy modification (Category D), while 40% were classified as high risk (Category X). In terms of clinical significance, the majority of interactions (67%) were classified as major, indicating a high potential for serious adverse outcomes. This aligns with findings from Dunn et al.,⁴⁹where major bleeding complications were a significant concern, emphasizing the need to avoid certain drug combinations due to their serious clinical consequences. The predominance of pharmacodynamic interactions (60%) suggests that most DDIs involved additive effects on coagulation pathways, thereby increasing the risk of bleeding. A similar pattern has been consistently reported, with pharmacodynamic interactions being the most commonly observed.^45,48-49 This contrasts with a retrospective study conducted in India, which reported that most interactions were pharmacokinetic (39%) and moderate in severity (70%).⁴⁶

Another important highlight was the encouraging trends in clinical management and safety monitoring of patients receiving antithrombotic therapy. Notably, platelet count monitoring was conducted in 94% of patients, reflecting strong adherence to safety protocols and a proactive approach to detecting early signs of thrombocytopenia or bleeding risk. Monitoring of PT and INR was performed in 73% and 72% of patients, respectively, indicating careful oversight of coagulation status, particularly in those treated with warfarin or other vitamin K antagonists. Renal function assessment was nearly universal (98%), which is commendable given the renal elimination pathways of many antithrombotic agents, including LMWHs and DOACs. Hepatic function monitoring was also performed in a significant proportion of patients (78%), underscoring a thorough and individualized approach to therapy. These practices are well aligned with current cardiology guidelines and evidence-based recommendations for the safe use of antithrombotic medications.⁵⁰By contrast, aPTT monitoring was less frequent (59%) despite its role in assessing heparin activity. D-dimer, a marker of clot formation and fibrinolysis, was tested in only 40% of patients. Monitoring of Protein C and Protein S was very limited, with just 1% of patients evaluated for each. Among patients assessed, only 1% achieved target INR and 3% met therapeutic aPTT, while 97% had subtherapeutic INR, indicating suboptimal anticoagulation management. No studies focusing exclusively on antithrombotics were found to confirm whether the observed monitoring frequencies or INR and aPTT attainment rates reflect standard practice or represent potential gaps in care, thereby limiting comparison and validation. Despite low therapeutic attainment, outcomes were favorable, suggesting that positive outcomes may still occur despite monitoring gaps, though this should be interpreted with caution.

Despite offering valuable insights, this study has several limitations that must be acknowledged. The sample size of 100 patients may limit the generalizability of the findings. The use of a convenience sampling approach may have impacted the representativeness of the study population. Additionally, the lack of randomization introduces the potential for selection bias, which could affect the validity of the results.

5. CONCLUSION:

This study provides real-world insights into the utilization patterns, safety concerns, and clinical outcomes associated with antithrombotic therapy in a tertiary care setting in the UAE. The observed variability in PDD, particularly for agents like enoxaparin and tirofiban, highlights deviations from WHO-defined DDDs and suggests the influence of clinical judgment, patient characteristics, and institutional protocols. A substantial proportion of patients experienced ADRs, most commonly hematuria and thrombocytopenia, with anticoagulants being the primary contributors. Additionally, DDIs were prevalent, with pharmacodynamic mechanisms most common and a significant number requiring therapy modification. The suboptimal monitoring of coagulation profiles and the low attainment of therapeutic INR and aPTT values emphasize the need for better monitoring strategies. Overall, these findings support the need for dose optimization, vigilant monitoring, and strengthened pharmacovigilance efforts to ensure the safe and effective use of antithrombotic agents in clinical practice.

6. LIST OF ABBREVIATIONS:

ACS - Acute Coronary Syndrome

ADRs - Adverse Drug Reactions

AF - Atrial Fibrillation

aPTT - Activated Partial Thromboplastin Time

ART - Adverse Reaction Terminology

ATC - Anatomical Therapeutic Chemical

BMI - Body Mass Index

CAD - Coronary Artery Disease

CCI - Charlson Comorbidity Index

DDD - Defined Daily Dose

DDIs - Drug-Drug Interactions

DOACs - Direct Oral Anticoagulants

HF - Heart Failure

ICU - Intensive Care Unit

IHD - Ischemic Heart Disease

INR - International Normalized Ratio

IQR - Interquartile Range

IU - International Units

LMWH - Low Molecular Weight Heparin

MI - Myocardial Infarction

NSAIDs - Non-Steroidal Anti-Inflammatory Drugs

PDD - Prescribed Daily Dose

PE - Pulmonary Embolism

PT - Prothrombin Time

SD - Standard Deviation

UAE - United Arab Emirates

UFH - Unfractionated Heparin

US - United States

WHO - World Health Organization

8. CONFLICT OF INTEREST:

The authors declare that the research was carried out without any commercial or financial ties that could be interpreted as a potential conflict of interest.

9. FUNDING:

The authors declare that no financial support was for the research, authorship, and/or publication of this article.

10. AUTHOR CONTRIBUTIONS:

Conceptualization, V.M.; Data collection, A.M.E.; Data curation and formal analysis, V.M. A.M.E.; Writing- Original draft preparation, V.M., J.M.L., A.M.E.; Writing- Review and editing, V.M., J.M.L.; Supervision, V.M. All authors have read and agreed to the published version of the manuscript.

11. DATA AVAILABILITY STATEMENT:

The data that support the findings of this study are available from the corresponding author, Dr. V. Menon, on special request.

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Received on 25.06.2025 Revised on 22.10.2025

Accepted on 27.12.2025 Published on 03.04.2026

Available online from April 06, 2026

Research J. Pharmacy and Technology. 2026;19(4):1785-1798.

DOI: 10.52711/0974-360X.2026.00256

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.

WHO Organ system classification	WHO-ART codes	ADRs	Number of ADRs (%)
Cardiac disorders	10008145	Chest pain	1 (4.76)
Nervous system disorders	10013241	Dizziness	1 (4.76)
	10019211	Severe headache	1 (4.76)
	10047128	Vertigo	1 (4.76)
Respiratory, thoracic, and mediastinal disorders	10013941	Dyspnea	1 (4.76)
Renal and urinary disorders	10019631	Hematuria	6 (28.57)
Skin and appendages disorders	10040785	Red colored skin lesion	1 (4.76)
Blood and lymphatic system disorders	10043554	Thrombocytopenia	4 (19.05)
General disorders and administration site conditions	10047320	Bleeding at the site of injection	1 (4.76)
Gastrointestinal disorders	10047700	Vomiting	2 (9.52)
Investigations	10003655	High aPTT	1 (4.76)
Investigations	10072454	High INR	1 (4.76)

Drug 1	Drug 2	Number of cases (%)	Category	Mechanism	Significance
Warfarin	Fenofibrate	1 (6.67)	D: Therapy modification	Pharmacokinetic	Major
Warfarin	Amiodarone	1 (6.67)	D: Therapy modification	Pharmacokinetic	Major
Warfarin	Dexketoprofen	1 (6.67)	D: Therapy modification	Pharmacodynamic	Moderate
Enoxaparin	Dexketoprofen	2 (13.33)	D: Therapy modification	Pharmacodynamic	Moderate
Enoxaparin	Loxoprofen	1 (6.67)	D: Therapy modification	Pharmacodynamic	Moderate
Enoxaparin	Rivaroxaban	1 (6.67)	X: Avoid combination	Pharmacodynamic	Major
Clopidogrel	Esomeprazole	3 (20.00)	X: Avoid combination	Pharmacokinetic	Major
Aspirin	Loxoprofen	1 (6.67)	D: Therapy modification	Pharmacodynamic	Moderate
Aspirin	Ticagrelor	1 (6.67)	D: Therapy modification	Pharmacodynamic	Major
Ticagrelor	Clopidogrel	2 (13.33)	X: Avoid combination	Pharmacodynamic	Major
Ticagrelor	Morphine	1 (6.67)	D: Therapy modification	Pharmacokinetic	Major

Variables	Categories	Number of patients (%)
Coagulation profile
Whether platelet count was monitored or not?	Yes	94 (94.00)
Whether platelet count was monitored or not?	No	6 (6.00)
Whether INR was monitored or not?	Yes	72 (72.00)
Whether INR was monitored or not?	No	28 (28.00)
Whether PT was monitored or not?	Yes	73 (73.00)
Whether PT was monitored or not?	No	27 (27.00)
Whether aPTT was monitored or not?	Yes	59 (59.00)
Whether aPTT was monitored or not?	No	41 (41.00)
Whether D-dimer was monitored or not?	Yes	40 (40.00)
Whether D-dimer was monitored or not?	No	60 (60.00)
Whether Protein S was monitored or not?	Yes	1 (1.00)
Whether Protein S was monitored or not?	No	99 (99.00)
Whether Protein C was monitored or not?	Yes	1 (1.00)
Whether Protein C was monitored or not?	No	99 (99.00)
Other laboratory investigations
Whether renal function was monitored before administering antithrombotics?	Yes	98 (98.00)
	No	2 (2.00)
Whether hepatic function was monitored before administering antithrombotics?	Yes	78 (78.00)
	No	22 (22.00)
Clinical outcome
Outcome	Recovered and discharged	94 (94.00)
	Discharged against medical advice	6 (6.00)
	Died	0 (0.00)
Minor bleeding complications were found?	Yes	8 (8.00)
Minor bleeding complications were found?	No	92 (92.00)
Major or life-threatening bleeding complications were found?	Yes	0 (0.00)
	No	100 (100.00)
The target INR was achieved? (n=72)	Below therapeutic range (< 2)	70 (97.22)
	Within therapeutic range (2-3)	1 (1.39)
	Above therapeutic range (> 3)	1 (1.39)
The target aPTT was achieved? (n=59)	Below therapeutic range (< 50)	57 (96.61)
	Within therapeutic range (50-90)	2 (3.39)
	Above therapeutic range (> 90)	0 (0)